The present invention relates to an improved dermal filler. In particular the present invention relates to an injectable, high viscosity dermal filler formulated with a botulinum toxin.
A pharmaceutical composition (synonymously a formulation or a composition) is a formulation which contains at least one active ingredient (for example a botulinum neurotoxin) as well as, for example, one or more excipients, buffers, carriers, stabilizers, preservatives and/or bulking agents, and is suitable for administration to a human patient to achieve a desired effect or result. The pharmaceutical compositions disclosed herein have cosmetic utility.
Movement of the face due to contractions of muscles underlying the skin can result in facial wrinkles. For example, repeated elevation of the brow by contraction of the frontalis muscle can cause brow furrows. Dermal fillers made from various substances have been used to treat facial wrinkles. Collagen based dermal fillers include ZYDERM® (Allergan, Inc., Irvine, Calif.), ZYPLAST® (Allergan, Inc., Irvine, Calif.), COSMODERM® (Allergan, Inc., Irvine, Calif.), COSMOPLAST® (Allergan, Inc. Irvine, Calif.) and Autologen (Collagenesis, Inc., Boca Raton, Fla.). Polylactic acid dermal fillers include SCULPTRA® (Sanofi-Aventis, Bridgewater, N.J.). Calcium hydroxyl apatite dermal fillers include RADIESSE® (BioForm Medical, Inc., San Mateo, Calif.). Hyaluronic acid dermal fillers include HYLAFORM® (Genzvme Corp., Cambridge, Mass.), RESTYLANE® (HA North America Sales AB, Scottsdale, Ariz.) and JUVEDERM® (Allergan, Inc., Irvine, Calif.). JUVEDERM® comprises a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenized gel consisting of cross-linked hyaluronic acid formulated at a concentration of 24 mg/ml in a physiologic buffer.
Electromyographic methods have been used to study the activity of various facial muscles which can cause facial wrinkles. See e.g. Fridlund A. et al., Guidelines for Human Electromyographic Research, Psychophysiology 1986; 23(5): 567-590; Vitti M, et al., Electromyographic Investigation of Procerus and Frontalis Muscles, Electromyogr. Clin. Neurophysiol. 1976, 16: 227-236, and; Tassinary L. et al., A Psychometric Study of Surface Electrode Placements for Facial Electromyographic Recording: I. The Brow and Cheek Muscle Regions, Psychophysiology 1989; 26(1): 1-16.
In particular, electromyography, including surface electromyography (sEMG) has been used to investigate activity of the frontalis muscle and resultant brow displacement. See e.g. van Boxtel A, et al., Amplitude and bandwidth of the frontalis surface EMG: Effects of electrode parameters, Psychophysiology 1984; 21(6): 699-707, and; Pennock J. D., et al., Relationship between muscle activity of the frontalis and the associated brow displacement, Plast Reconstr Surg November 1999; 104(6): 1789-1797.
Additionally, it is known to study skin topography (i.e. facial wrinkles) by making a silicone rubber negative replica (a mold) of a skin surface area. The mold captures three dimensional details of the skin surface and computerized image analysis of skin line density, depths and length analysis shown can be carried out thereon. Grove, G. L., et al, Objective method for assessing skin surface topography noninvasively, chapter one, pages 1-32 of Cutaneous Investigation in Health and Disease, edited by Leveque J-L., Marcel Dekker, Inc. (1989). The same silicone rubber impression method has been used to examine the effect of a topical cream to treat photodamaged skin, as by reduction of periorbital (crows feet) wrinkles. Leyden J. J., et al., Treatment of photodamaged facial skin with topical tretinoin, J Am Acad Dermatol 1989; 21(3) (part 2): 638-644, and; Grove G. L., et al., Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream, J Am Acad Dermatol 1991; 25(2) (part 1): 231-237. See also U.S. Pat. Nos. 6,688,311; 7,234,469, and; 7,140,371.
Hyaluronic Acid
Hyaluronic acid (also called hyaluronan or sodium hyaluronate) is a naturally occurring polysaccharide found in joints, connective tissue and the eye. Hyaluronic acid is a glycosaminoglycan (a mucopolysaccharide) which is a long unbranched polysaccharide composed of repeating dimeric units of glucuronic acid and N acetyl glucosamine. U.S. Pat. Nos. 4,636,524; 4,713,448; 5,099,013, and 5,143,724 disclose particular hyaluronic acids and methods for making them.
Hyaluronic acid has known therapeutic and cosmetic uses. For example, intra-articular use of hyaluronic acid as a viscosupplement to treat osteoarthritis joint pain is known (eg ORTHOVISC® (Anika, Woburn, Mass.), DUROLANE® (Q-Med AB, Uppsala, SE/Smith & Nephew, Rotkreuz, CH), HYALGAN® (Sanofi-Aventis, Bridgewater, N.J.), Hylastan (Genzyme Corp., Cambridge, Mass.), SUPARTZ® (Seikagaku, Tokyo, JP/Smith & Nephew, Rotkreuz, CH), SYNVISC® (Genzyme Corp., Cambridge, Mass.), and EUFLEXXA® (Ferring B.V., Hoofddorp, NL)). Hyaluronic acid is also used cosmetically as an injectable soft tissue dermal filler (eg JUVEDERM® ) to treat facial rhytides.
The duration of the wrinkle alleviating effect of action of a dermal filler is typically about one year or less, and can be only a few months for eg dermal fillers administered in a perioral area. The duration of the wrinkle alleviating effect of action of a hyaluronic acid dermal filler is influenced by mechanical stress upon enzymatic degradation of the hyaluronic acid, as well as by the rate of clearance of the hyaluronic acid from the site of injection via the extensive tissue lymphatic vessels. Mechanical stress degradation of the injected hyaluronic acid is especially notable in areas of the face which experience frequent muscle contraction, such as around the mouth, eyes and the forehead. In particular, the dermis overlying the orbicularis oris muscle in the perioral area is a site of high mechanical stress due to frequent muscle contraction. Such repetitive mechanical stress can lead to movement of the injected hyaluronic acid from the intended site of action and untimely (premature) degradation of the dermal filler polymer.
U.S. patent applications which disclose use of therapeutic agent formulated with a hyaluronic acid include application Ser. No. 10/966,764, filed Oct. 14, 2004, application Ser. No. 11/091,977, filed Mar. 28, 2005, application Ser. No. 11/354,415, Feb. 14, 2006, application Ser. No. 11/741,366, filed Apr. 27, 2007, application Ser. No. 11/828,561, filed Jul. 26, 2007, application Ser. No. 11/039,192, filed Jan. 19, 2005, application Ser. No. 11/116,698, filed Apr. 27, 2005, application Ser. No. 11/695,527, filed Apr. 2, 2007, and application Ser. No. 11/742,350, filed Apr. 30, 2007.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin called botulinum neurotoxin toxin which causes a neuroparalytic illness in humans and animals referred to as botulism. Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of a commercially available botulinum toxin type A (purified neurotoxin complex)1 is a LD50 in mice (i.e. 1 unit). One unit of BOTOX® contains about 50 picograms (about 56 attomoles) of botulinum toxin type A complex. One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 20 grams each. Available from Allergan, Inc., of Irvine, Calif. under the tradename BOTOX® in 100 unit vials)
Seven, generally immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum toxins have been used for the treatment of various therapeutic and cosmetic conditions. A botulinum toxin type A (Allergan, Inc., BOTOX®) has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, cervical dystonia, hyperhydrosis and glabellar lines.
The molecular weight of the neurotoxic component of a botulinum toxin complex is about 150 kD. Botulinum toxin is typically made by the Clostridial botulinum bacterium as a complex comprising the 150 kD botulinum toxin protein molecule and associated non-toxin proteins. Thus, a botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD complex forms.
It is known that injection of a botulinum toxin into facial muscles can, by weakening the injected muscles, result in a decrease of hyperkinetic wrinkles in the skin overlying the paralyzed muscles. See e.g. Carruthers A. et al., The treatment of glabellar furrows with botulinum A exotoxin, J Dermatol Surg Oncol January 1990;16(1):83. Thus, botulinum toxin has been injected into facial muscles, such as the orbicularis oculis, corrugator supercilii and frontalis muscles for the cosmetic purpose of reducing certain facial wrinkles, and it is known to use electromyographic and/or photographic techniques to assess the efficacy of such injections. Guerrissi J. et al., Local injection into mimetic muscles of botulinum toxin A for the treatment of facial lines, Ann Plast Surg 1997;39(5):447-53. Electromyography has also been used to assess the effect of injection of a botulinum toxin into the sternocleidomastoid muscle for treatment of cervical dystonia. Dressler D. et al., Electromyographic quantification of the paralysing effect of botulinum toxin in the sternocleidomastoid muscle, Eur Neurol 2000; 43: 13-16. In sEMG the surface electrodes are placed at fixed distances from the injection point, typically 1 cm and 3 cm from the injection point. The surface electrodes can be used to measure the amplitude and area of a compound muscle action potential (CMAP) during maximal voluntary contraction of the injected muscle. One expects to find that CMAP decreases with the onset of muscle paralytic effect and to increase as the paralytic effect wears off.
Photographic methods, such as digital image analysis, have been used to determine efficacy of a botulinum toxin to treat hyperkinetic facial lines. Heckmann M., et al., Quantification of the efficacy of botulinum toxin type A by digital image analysis, J Am Acad Dermatol 2001; 45: 508-514.
A commercially available botulinum toxin containing pharmaceutical composition is sold under the trademark BOTOX® (available from Allergan, Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxin type A complex, albumin and sodium chloride packaged in sterile, vacuum-dried form. Each vial of BOTOX® contains about 100 units (U) of Clostridium botulinum toxin type A purified neurotoxin complex, 0.5 milligrams of human serum albumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative. Other commercially available botulinum neurotoxins approved for use in humans include DYSPORT® (Beaufour Ipsen, Porton Down, England) XEOMIN® (Merz Pharmaceuticals GmbH, Frankfurt, Germany) and MYOBLOC® (Solstice Neurosciences, San Francisco, Calif.).
What is therefore needed is an improved dermal filler formulation which has a longer duration (i.e. more than three months in a perioral area) wrinkle alleviating effect upon injection (subdermal) of the dermal filler, for example by decreasing the mechanical stress and enzymatic degradation of the injected dermal filler.